Expression of DNA Repair Genes is Sensitive Marker for Oxidative Stress

Ivan Rusyn, MD, Ph.D. and James Swenberg, DVM, Ph.D.
University of North Carolina at Chapel Hill
K22ES11660, U19ES11391, P42ES05948, and P30ES10126

Background: Oxidative damage to DNA is known to be one of the mechanisms leading to the development of cancer after exposure to environmental agents. Studies have shown that chemical carcinogens that increase the production of reactive oxygen species also induce the formation of oxidative DNA lesions. All aerobic organisms have evolved methods to repair this damage known as DNA adducts. Adducts have been used extensively as markers for environmental damage to DNA; however, in many studies oxidants fail to produce adducts. Thus, these researchers thought that expression of genes involved in DNA repair might be a more sensitive marker for exposure and effect.

Advance: To test the hypothesis, mice were given the chemical carcinogen and peroxisome proliferator WY-14,463. Peroxisomes are intracellular organelles that metabolize lipids and are found in high concentrations in liver cells. Peroxisome proliferators are compounds that stimulate a marked increase in the number and size of peroxisomes in liver tissue and are thought to contribute to carcinogenesis by generating reacting oxygen species that damage DNA. Treatment with WY-14,463 failed to produce differences in a number of conventional end points that are commonly used to assess oxidative DNA damage. However, there was a marked increase in the expression of genes responsible for a specific pathway of DNA repair that removes oxidative damage. Furthermore, this novel marker of oxidative DNA damage was used to elucidate how WY-14,463 causes production of oxidants that damage DNA.

Implication: The studies suggest that gene expression analyses can be used as sensitive markers for chemically-induced oxidative DNA damage. In this study, the gene expression changes for a DNA repair pathway specific for removal of oxidized lesions were seen at a dose that did not produce common markers of oxidative damage; therefore, these gene expression analyses could be a used as a more sensitive measure. Additional studies are needed to corroborate these results in other model systems where oxidative damage to DNA is thought to play a role in cancer but no firm experimental evidence is yet available.

Citation: Rusyn I, Asakura S, Pachkowski B, Bradford BU, Denissenko MF, Peters JM, Holland SM, Reddy JK, Cunningham ML, Swenberg JA. Expression of base excision DNA repair genes is a sensitive biomarker for in vivo detection of chemical-induced chronic oxidative stress: identification of the molecular source of radicals responsible for DNA damage by peroxisome proliferators. Cancer Res. 2004 Feb 1;64(3):1050-7.